A Novel KIDINS220 Pathogenic Variant Associated with the Syndromic Spastic Paraplegia SINO: An Expansion of the Brain Malformation Spectrum and a Literature Review

Abstract

Background/objectives: Identifying novel variants in very rare disease genes can be challenging when patients exhibit a complex phenotype that expands the one described, and we provide such an example here. A few terminal truncating variants in KIDINS220 cause spastic paraplegia (SP), intellectual disability (ID), nystagmus, and obesity (SINO, MIM #617296). Prompted by the result of next-generation sequencing on a patient referred for SP associated with complex brain dysmorphisms, we reviewed the phenotype of SINO patients focusing on their brain malformations, mainly described in prenatal age and first years of life, and tried to understand if the predicted effect of the mutant kidins220 may have caused them.

Methods: We performed whole exome sequencing (WES) and a literature and mutation databases review.

Results: We report a young adult with SP, severe ID, strabismus, and macrocephaly exhibiting brain malformations at follow-up, partially overlapping with those described in TUBB3 tubulinopathy. WES analysis of the proband and parents identified the heterozygous de novo variant (NM_020738.4: c. 4144G > T) p. Glu 1382* in KIDINS220 that was predicted to be causative of SINO.

Conclusions: The progression of myelination and the development of brain structures turned out to be crucial for identifying, at follow-up, the whole KIDINS220-related brain malformations. The truncated proteins associated with SINO lack a portion fundamental for the interaction of kidins220 with tubulins and microtubule-associated proteins. The complexity of the brain malformations displayed by our patient, and possibly by other reported SINO patients, could result from an impaired dynamic modulation of the microtubule cytoskeleton during embryogenesis. Brain malformations must be considered as part of the SINO spectrum phenotype.

Keywords: axon guidance defects; macrocephaly; obesity; scaffold protein; spastic paraplegia; tubulin-related disorders.

Figure 1

Brain MRI scans of the 17-year-old patient (bottom panel) compared to an age-matched control (upper panel): (A) transverse T2 SE, (B) color fractional anisotropy, (C) sagittal T1 SE, (D) transverse T2 SE, (E) coronal T2 SE. (A) Lateral ventricle enlargement with dysmorphic appearance; the dysmorphic and hypoplasic anterior limb of the internal capsule (light blue arrow) with partial fusion of lenticular nucleus and caudate nucleus head (red arrow). (B) Thinning of the corticospinal tract is evident at the level of the posterior arm of the internal capsule (white head arrow). (C) Thinned and dysplasic corpus callosum. (C,D) Pontomesemcephalic hypoplasia with defect of segmentation and dysmorphic appearance. (E) Septum pellucidum agenesis, thickened and dysmorphic fornices, anterior commissure agenesis, optic chiasm hypoplasia. (A,E) Simplified pattern of gyration of the frontal lobes with global volumetric reduction.

Figure 2

KIDINS220 pathogenic variants associated with SINO. (A) Electropherogram showing the de novo nonsense heterozygous variant. (B) The genomic structure of KIDINS220 includes 30 exons. The approximate position of the pathogenic variants, based on RefSeq NM_020738.4, is indicated; the novel variant reported here is highlighted in bold. (C) Schematic structure of Kidins220/ARMS with its six putative domains: I, ankyrin repeats domain; II, KAP (kidins220/ARMS and PifA)-NTPase domain; III, proline-rich domain: the region crucial for docking the CRKL adaptor protein is necessary for the sustained activation of MAPK signaling; IV, SAM (sterile α motif) domain; V, KIM (KLC-interacting motif) domain; KLC, kinesin light chain; VI, PDZ (PSD-95, Dlg, and ZO-1 protein)-binding motif domain. Domains III to VI constitute the C-terminal domain. Triangles show the approximate position of the eleven pathogenic variants in the protein domains. The impact of the predicted splice variant in intron 27 has yet to be studied, so it is not reported. P, patient; TM, transmembrane; *, variants in compound heterozygosity. References: Josifova 2016 [6], Yang 2018 [7], Zhang 2021 [8], Zhao 2019 [9], Mero 2017 [10], Jacquemin 2021 [11], El-Dessouky 2020 [12], Brady 2022 [13].